JP2006176503A - Therapeutic agent for alzheimer's disease accompanied with cerebrovascular disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic agent for Alzheimer's disease accompanied with cerebrovascular disorder. <P>SOLUTION: The therapeutic agent for Alzheimer's disease accompanied with cerebrovascular disorder is obtained by combinedly using a compound having cholinesterase inhibiting action or a pharmaceutically permissible salt thereof or their solvate, and Kamiuntanto or one of its constituent crude medicine. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder.

Cholinesterase is a general term for enzymes that are widely distributed in the living body and hydrolyze choline esters such as acetylcholine, which is a neurotransmitter. The enzyme activity is inhibited by physostigmine (10 ^-5 mol / L). There are various types of cholinesterase, including true cholinesterase that specifically degrades acetylcholine present in nerve tissue, red blood cells, muscles, etc., and choline ester present in serum, liver, pancreas, etc. Two types of pseudocholinesterase are known. The former is called acetylcholinesterase (EC 3.1.1.7), and has the property of hydrolyzing acetylcholine more rapidly than other choline esters and undergoing substrate inhibition. On the other hand, the latter has a property of hydrolyzing many choline esters other than acetylcholine and esters not containing choline.

  The cholinesterase inhibitor has an action of suppressing acetylcholine hydrolysis in vivo by cholinesterase, increasing acetylcholine in the synaptic cleft, and increasing acetylcholine transmission. In particular, donepezil hydrochloride, which is an acetylcholinesterase inhibitor, increases the amount of acetylcholine in the brain and is widely used as a therapeutic agent for Alzheimer-type senile dementia (Patent Document 1).

  By the way, Kami Onsen is a traditional Chinese medicine written in the Japanese medicine book of the Edo period. Stress, decreased gastrointestinal function, gastrointestinal weakness, etc. may lead to irritability or mental anxiety, accompanied by insomnia such as poor sleep, waking up early, and sleeplessness, and depression such as nausea, depression, palpitation, and vomiting Used to treat patients. Of the 13 herbal medicines in Kami Onsen (half summer, Chen bark, ginger, bamboo shoots, cocoon, ambition, acid jinjin, cocoon, carrot, licorice, daikon, jio, ginseng) In cholinergic neurons, choline acetyltransferase (ChAT) activity is believed to have an enhancing effect.

From past studies, donepezil hydrochloride competitively inhibits acetylcholinesterase, an acetylcholine degrading system, and Kamibokujito increases expression of acetylcholine synthase (ChAT), an acetylcholine synthesizing system, at the mRNA level. It is known to increase acetylcholine concentration in the synaptic cleft. And it is known that the increase in acetylcholine enhances the neurotransmission function, and thus shows the effect of improving the cognitive function of Alzheimer's disease (AD) patients (Non-Patent Documents 1 to 3). However, since there is a feedback mechanism by inhibiting the degradation system of acetylcholine, it has been proved by animal experiments that acetylcholine synthesis is reduced and the acetylcholine concentration cannot be increased efficiently (Non-patent Document 4).
Japanese Patent No. 2578475 Yabe T, et al. Phytomedicine 2: 41-46, 1995 Wang Q, et al. Phytomedicine 7: 253-258, 2000 Suzuki T, et al. Alzheimer's Rep. 4: 177-182, 2001. Somani SM, et al. Pharmacol Biochem Behav. 39 (2): 337-43, 1991.

  An object of the present invention is to provide a therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder.

  The present inventor combined the previous findings of an increase in the concentration of acetylcholine (ACh) by a cholinesterase (ChE) inhibitor and an increase in the concentration of ACh by acetyltransferase (ChAT) activity increase by Kamibokujito, The hypothesis that cognitive function was further improved by increasing the ACh concentration in the synaptic crevice by simultaneously operating, was investigated. The present inventor measured cognitive function by ADAS-cog. And brain function by cerebral blood flow scintigram, and compared the effect of combination therapy with monotherapy. As a result, it was clarified that the combined use or combination of ChE inhibitor and Kamibokujito showed an effect of improving cognitive function and an improvement of cerebral blood flow in the frontal lobe. Because basal ganglia infarction is the part where blood flow is reduced most by white matter lesions, it is important to use or combine both ChE inhibitor and Kamibokubyoto for cerebral dysfunction associated with cerebrovascular disorders, especially cerebrovascular disorders. It has been shown to be effective in the treatment of Alzheimer's disease accompanied by the present invention, and the present invention has been completed. That is, the present invention is as follows.

(1) A cerebral blood flow improving agent comprising a compound having a cholinesterase inhibitory action, a pharmacologically acceptable salt thereof, or a solvate thereof, and at least one of Kamiyutobyoto or its constituent crude drugs.
Examples of the brain include the frontal lobe.

(2) A cognitive dysfunction associated with cerebrovascular disorder, comprising a compound having a cholinesterase inhibitory action, a pharmacologically acceptable salt thereof or a solvate thereof, and at least one of Kamiyokuto or its constituent crude drugs. Remedy.

(3) A therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder, comprising a compound having a cholinesterase inhibitory action or a pharmacologically acceptable salt thereof, and at least one of Kamientobyoto or its constituent crude drugs.

Examples of the compound having a cholinesterase inhibitory action used in the improving agent or therapeutic agent include compounds having an acetylcholinesterase inhibitory action.
The salt is preferably a hydrochloride. As said compound, the cyclic amine derivative represented with the following general formula can be illustrated.
[Where,
J represents (a) a substituted or unsubstituted group; (1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexyl group, (6) quinoxalyl group Or (7) a furyl group,
(B) a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group; (1) indanyl, (2) indanonyl, (3) indenyl, (4) Indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, formula (9)

(C) a monovalent group derived from a cyclic amide compound,
(D) Lower alkyl group, or (e) Formula R ¹ —CH═CH— (wherein R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group)
Means a group represented by
(Wherein R ³ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group),
A hydrogen atom or a methyl group is meant. }, A group represented by formula = (CH—CH═CH) _b — (wherein b represents an integer of 1 to 3), formula = CH— (CH ₂ ) _c — (where c is 0) Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5),
Or a group represented by the formula -NH-, a group represented by the formula -O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.
T means a nitrogen atom or a carbon atom.

K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group.
q means an integer of 1 to 3.

In particular, the above J is a substituted or unsubstituted (1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexyl group, (6) quinoxalyl group and (7 ) It may be one group selected from the group consisting of furyl groups, and J may be a monovalent group derived from a cyclic amide compound.

In addition, the compound may be a cyclic amine derivative represented by the following general formula.
[Where,
J ¹ is a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group; (1) indanyl, (2) indanonyl, (3) indenyl, (4) Indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, formula (9)
(Wherein R ³ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group),
A hydrogen atom or a methyl group is meant. }, A group represented by formula = (CH—CH═CH) _b — (wherein b represents an integer of 1 to 3), formula = CH— (CH ₂ ) _c — (where c is 0) Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5),
Or a group represented by the formula -NH-, a group represented by the formula -O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.
T means a nitrogen atom or a carbon atom.
K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group.
q means an integer of 1 to 3.
In particular, B is the formula
A hydrogen atom or a methyl group is meant. A group represented by the formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a formula = CH- (CH ₂ ) _c- (wherein C represents an integer of 0 or 1 to 9) or a group represented by the formula = (CH-CH) _d = (wherein d represents an integer of 0 or 1 to 5). There may be.

Furthermore, the compound may be a cyclic amine derivative represented by the following general formula.
[Where,
J ¹ is a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group; (1) indanyl, (2) indanonyl, (3) indenyl, (4) Indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, formula (9)
A hydrogen atom or a methyl group is meant. A group represented by the formula: —CH═CH— (CH) _n R ² — (wherein n represents 0 or an integer of 1 to 10, and R ² represents a hydrogen atom or a methyl group). A group represented by the formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a formula = CH- (CH ₂ ) _c- (where c is Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5).
K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group. ]
In particular, the K may be a substituted or unsubstituted arylalkyl group or a phenyl group, and the J ¹ is selected from the group consisting of monovalent and divalent groups derived from indanonyl, indenyl and indandionyl. One group may be used. Here, J ¹ is preferably an indanonyl group which may have a lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms as a substituent.

The cyclic amine derivatives are 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanone) 2-Iridenyl) methylpiperidine, 1-benzyl-4-((5-methoxy-1-indanone) -2-yl) methylpiperidine, 1-benzyl-4-((5,6-methylenedioxy-1- Indanone) -2-yl) methylpiperidine, 1- (m-nitrobenzyl) -4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine, 1-cyclohexylmethyl-4-(( 5,6-Dimethoxy-1-indanone) -2-yl) methylpiperidine, 1- (m-fluorobenzyl) -4-((5,6-dimethoxy-1-indanone) -2-y ) Methylpiperidine, 1-benzyl-4- (3-((5,6-dimethoxy-1-indanone) -2-yl) propyl) piperidine, 1-benzyl-4-((5-isopropoxy-6-methoxy) -1-indanone) -2-yl) methylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-ylidenyl) propenylpiperidine, and 1-benzyl-4-((5 6-dimethoxy-1,3-indandione) -2-yl) propenylpiperidine may be at least one selected from the group consisting of 1-benzyl-4-((5,6-dimethoxy-1-indanone) ) -2-yl) methylpiperidine is preferred, and its hydrochloride is more preferred.
Examples of the compound having an inhibitory action on acetylcholinesterase include galantamine, tacrine, physostigmine and rivastigmine.

  In the present invention, the constituent herbal medicine of the above-mentioned Kamibokuto may contain at least a long distance.

(4) The compound having a cholinesterase inhibitory action of the present invention, a pharmacologically acceptable salt thereof, or a solvate thereof, and at least one of Kamibokuto or its constituent crude drugs are administered to a patient. To treat Alzheimer's disease with cerebrovascular disorders.

  The present invention provides a therapeutic agent for Alzheimer's disease comprising a compound having a cholinesterase (ChE) inhibitory action or a pharmacologically acceptable salt thereof, and at least one of Kamiyutobyoto or its constituent crude drugs. The therapeutic agent for Alzheimer's disease of the present invention is useful as a new therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder by the combined use of a compound having a ChE inhibitory action and Kamisentobileto.

  In the present invention, a combination of a cholinesterase (ChE) inhibitor and Kamibokujito suppresses the degradation of acetylcholine (ACh) and increases the concentration of ACh in the synaptic cleft, thereby causing Alzheimer's disease patients, particularly cerebrovascular disorders. It was completed by finding that the cognitive function of the accompanying Alzheimer's disease patient is improved and the cerebral blood flow is improved.

  Therefore, the present invention provides a compound having an action of suppressing the degradation of ACh and increasing the concentration of ACh, that is, a compound having a ChE inhibitory action or a pharmacologically acceptable salt thereof and a choline acetyltransferase expression-inducing action. The present invention provides a therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder, which is combined or blended with hot gyoto as an active ingredient.

1. Compound having cholinesterase inhibitory activity The compound having ChE inhibitory activity in the present invention means a ChE inhibitory activity, that is, a substance that reversibly or irreversibly inhibits the activity of ChE. In the present invention, ChE includes acetylcholinesterase (AChE) (EC3.1.1.7), butyrylcholinesterase, and the like. Preferred features of the compound having ChE inhibitory activity of the present invention include a high selectivity for AChE over butyrylcholinesterase and an ability to cross the blood-brain barrier. It can be mentioned that the dose required for treatment does not cause serious side effects.

  As the Alzheimer's disease therapeutic agent in the present invention, preferred compounds to be used in combination with or in combination with Kamibokujito include compounds that inhibit ChE, particularly AChE, or pharmacologically acceptable salts thereof.

  Compounds that inhibit ChE of the present invention include donepezil (ARICEPT®), galantamine (Reminyl®), tacrine (Cognex®) )), Rivastigmine (Exelon®), zifrosilone (US Pat. No. 5,693,668), physostigmine (Synapton), ipidacrine (US Pat. No. 4,550,113) Description), quilostigmine, Metrifonate (Promem) (US Pat. No. 4,950,658), eptastigmine, vernacrine, tolserine, cymserine (US Pat. No. 6,410,747) Description), mestinone, icopezil (icopez) il) (US Pat. No. 5,750,542), TAK-147 (J. Med. Chem., 37 (15), 2292-2299, 1994, Japanese Patent No. 2650537, US Pat. No. 5,273,974) Huperzine A (Drugs Fut., 24, 647-663, 1999), stacofylline (US Pat. No. 4,599,338), thiatolserine, Neostigmine, eseroline Or thiacymserine, 8- [3- [1-[(3-fluorophenyl) methyl] -4-piperidinyl] -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3 , 2,1-ij] quinolin-4-one (Japanese Patent No. 3512786), phenserine, or ZT-1. Alternatively, it may be a derivative of the compound or a prodrug of the compound. Furthermore, a pharmacologically acceptable salt of the compound, the derivative or the prodrug or a solvate thereof is also included as a preferable embodiment of the compound having a ChE inhibitory action. Furthermore, examples of the compound having a ChE inhibitory action include compounds having a ChE inhibitory action described in International Publication No. 00/18391 pamphlet.

  Galantamine and its derivatives are disclosed in U.S. Pat. No. 4,663,318, WO 88/08708, WO 97/03987, U.S. Pat. No. 6,316,439, U.S. Pat. No. 6,323,195, U.S. Pat. No. 6323196 and the like. Tacrine and its derivatives are disclosed in US Pat. No. 4,631,286, US Pat. No. 4,695,573, US Pat. No. 4,754,050, WO 88/02256, US Pat. No. 4,835,275, US Pat. No. 4,839,364, U.S. Pat. No. 4,999,430, International Publication No. WO 97/21681, and the like. Physostigmine and its derivatives are disclosed in US Pat. No. 5,077,289, US Pat. No. 5,177,101, US Pat. No. 5,302,721, JP-A-5-306286, US Pat. No. 7,166,824, and European Patent No. 298202. Description, WO 98/27096, J. Pharm. Exp. Therap., 249 (1), 194-202, 1989, and the like. Rivastigmine and its derivatives are described in EP 193926, WO 98/26775, WO 98/27055 and the like.

  Here, “prodrug” is an inactive substance of “active substance of drug” (meaning “drug” corresponding to prodrug) for the purpose of improving bioavailability and reducing side effects. It is a drug that has been chemically modified and is metabolized to the active substance in the body after absorption and exerts its action. Thus, the term “prodrug” has a lower intrinsic activity than the corresponding “drug” but is spontaneously chemical or enzyme-catalyzed or metabolic when administered to a biological system. As a result, it refers to any compound that produces the “drug” substance. As the prodrug, the amino group, hydroxyl group, carboxyl group, etc. of the compound exemplified above or the compound represented by the following general formula is acylated, alkylated, phosphorylated, borated, carbonated, esterified, amidated. Or various prodrugs, such as a urethanized compound, can be illustrated. However, the exemplified groups are not comprehensive and merely exemplary, and those skilled in the art can prepare various other known prodrugs from the compounds exemplified above or the compounds represented by the following general formula by known methods. can do. Prodrugs composed of the compounds exemplified above or compounds represented by the following general formula are included within the scope of the present invention.

  In the present invention, as a more preferred example of a compound having ChE inhibitory action, particularly AChE inhibitory action, a cyclic amine derivative represented by the following general formula (I), a pharmacologically acceptable salt thereof or a solvent thereof: Japanese products are listed. The salt of these compounds is preferably hydrochloride. The compound having ChE inhibitory action is preferably 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine (donepezil) and pharmacologically acceptable salts thereof, and their Solvates, particularly preferably 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine hydrochloride (donepezil hydrochloride), ie ARICEPT (registered trademark) ).

<About General Formula (I)>
Formula (I)

[Wherein, J means a group shown in the following groups (a) to (e).
(A) a substituted or unsubstituted group shown below;
(1) phenyl group,
(2) pyridyl group,
(3) pyrazyl group,
(4) quinolyl group,
(5) cyclohexyl group,
(6) quinoxalyl group or
(7) furyl group,
(B) a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group;
(1) Indanyl,
(2) Indanonyl,
(3) indenyl,
(4) Indenonyl,
(5) indandionyl,
(6) tetralonyl,
(7) Benzsuberonil,
(8) Indanolyl,
Equation (9)

(C) a monovalent group derived from a cyclic amide compound,
(D) A lower alkyl group, or (e) a group represented by the formula R ¹ —CH═CH— (wherein R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group).

(Wherein R ³ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group),

A hydrogen atom or a methyl group is meant. }, A group represented by formula = (CH—CH═CH) _b — (wherein b represents an integer of 1 to 3), formula = CH— (CH ₂ ) _c — (where c is 0) Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5),

Or a group represented by the formula -NH-, a group represented by the formula -O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.
T means a nitrogen atom or a carbon atom.

K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group.
q means an integer of 1 to 3.

In the present specification, the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group: sec-butyl group, tert-butyl group, pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl Group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl Group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethyl Propyl group, 1,2,2-trimethyl propyl group, 1-ethyl-1-methylpropyl group, means such as 1-ethyl-2-methylpropyl group. Among these, preferred groups include a methyl group, an ethyl group, a propyl group, and an isopropyl group, and the most preferred is a methyl group. The “lower alkyl group” is described in the above definition of the compound (I) of the present invention, for example, in the definitions of J, K, R ³ and R ⁴ .
In the present specification, the “lower alkoxy group” means a lower alkoxy group corresponding to the above lower alkyl group, such as a methoxy group or an ethoxy group.
In the present specification, the “lower alkoxycarbonyl group” means a lower alkoxy corresponding to the lower alkoxy group such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, an n-propoxycarbonyl group, and an n-butoxycarbonyl group. Means a carbonyl group.
In the present specification, the “cycloalkyl group” is a cyclic alkyl group having 4 to 10 carbon atoms, and examples thereof include, but are not limited to, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

<About J>
Group (a) in J: “Substituted or unsubstituted groups shown below; (1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexyl group, (6) In the definition of `` quinoxalyl group or (7) furyl group '', as the substituent,
A lower alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group;
A lower alkoxy group corresponding to the above lower alkyl group such as a methoxy group and an ethoxy group;
Nitro group; halogen such as chlorine, bromine and fluorine;
Carboxyl group;
A lower alkoxycarbonyl group corresponding to the above lower alkoxy group, such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, an n-propoxycarbonyl group, an n-butoxycarbonyl group;
An amino group;
A mono-lower alkylamino group;
Di-lower alkylamino group;
A carbamoyl group;
An acylamino group derived from an aliphatic saturated monocarboxylic acid having 1 to 6 carbon atoms, such as acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, pivaloylamino group;
A cycloalkyloxycarbonyl group such as a cyclohexyloxycarbonyl group;
A lower alkylaminocarbonyl group such as a methylaminocarbonyl group or an ethylaminocarbonyl group;
A lower alkylcarbonyloxy group corresponding to the lower alkyl group defined above, such as a methylcarbonyloxy group, an ethylcarbonyloxy group, an n-propylcarbonyloxy group;
A halogenated lower alkyl group typified by a trifluoromethyl group and the like;
Hydroxyl group;
Formyl group; lower alkoxy lower alkyl group such as ethoxymethyl group, methoxymethyl group, methoxyethyl group,
And so on. In the above description of the substituents, “lower alkyl group” and “lower alkoxy group” include all groups derived from the above definitions. (a) The groups (1) to (7) in the group may be substituted with 1 to 3 identical or different groups.

  Further, in the case of a phenyl group, the following case shall be included in the substituted phenyl group. That is,

E means a carbon atom or a nitrogen atom. ).
D is a lower alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and tert-butyl group;
A lower alkoxy group corresponding to the above lower alkyl group such as a methoxy group and an ethoxy group;
A nitro group;
Halogens such as chlorine, bromine, fluorine;
Carboxyl group;
A lower alkoxycarbonyl group corresponding to the above lower alkoxy group, such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, an n-propoxycarbonyl group, an n-butoxycarbonyl group;
An amino group;
A mono-lower alkylamino group;
Di-lower alkylamino group;
A carbamoyl group;
An acylamino group derived from an aliphatic saturated monocarboxylic acid having 1 to 6 carbon atoms, such as acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, pivaloylamino group;
A cycloalkyloxycarbonyl group such as a cyclohexyloxycarbonyl group;
A lower alkylaminocarbonyl group such as a methylaminocarbonyl group or an ethylaminocarbonyl group;
A lower alkylcarbonyloxy group corresponding to the lower alkyl group defined above, such as a methylcarbonyloxy group, an ethylcarbonyloxy group, an n-propylcarbonyloxy group;
A halogenated lower alkyl group typified by a trifluoromethyl group and the like;
Hydroxyl group;
Formyl group;
And lower alkoxy lower alkyl groups such as ethoxymethyl group, methoxymethyl group and methoxyethyl group. In the above description of the substituents, “lower alkyl group” and “lower alkoxy group” include all groups derived from the above definitions.

Among these, preferred substituents for the phenyl group include lower alkyl groups, lower alkoxy groups, nitro groups, halogenated lower alkyl groups, lower alkoxycarbonyl groups, formyl groups, hydroxyl groups, lower alkoxy lower alkyl groups, halogens, and benzoyl groups. , A benzylsulfonyl group, and the like. The substituents may be the same or different and two or more may be present.
Preferred examples of the substituent for the pyridyl group include a lower alkyl group, an amino group, and a halogen atom.
Preferred examples of the substituent for the pyrazyl group include a lower alkoxycarbonyl group, a carboxyl group, an acylamino group, a carbamoyl group, and a cycloalkyloxycarbonyl group.

  The pyridyl group as J is preferably a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, the pyrazyl group is preferably a 2-pyrazyl group, and the quinolyl group is preferably a 2-quinolyl group or a 3-quinolyl group. The quinoxalyl group is preferably a 2-quinoxalyl group or a 3-quinoxalyl group, and the furyl group is preferably a 2-furyl group.

  In the definition of J, typical examples of monovalent or divalent groups derived from (1) to (9) described in (b) group are as follows.

In the above series of formulas, t means 0 or an integer of 1 to 4, and indicates that the phenyl group is substituted with 0 or 1 to 4 groups represented by the same or different S. S represents one of the substituents in the definition of the J (a) group which is the same or different, or a hydrogen atom, preferably a hydrogen atom (unsubstituted), a lower alkyl group or a lower alkoxy group. Can do. Furthermore, it may be substituted with an alkylenedioxy group such as a methylenedioxy group or an ethylenedioxy group between adjacent carbons of the phenyl ring.
Of these, the preferred case is unsubstituted or substituted with 1 to 3 methoxy groups or isopropoxy groups, the substituted methylenedioxy group, and the most preferred is unsubstituted or methoxy. In this case, 1 to 3 groups are substituted.
The above indanolidenyl is an example of a divalent group in which the phenyl group in the definition of J (b) may be substituted. That is, it is a typical divalent group derived from indanonyl of (2) of J (b).

  In the definition of J, examples of the monovalent group derived from the cyclic amide compound (c) include quinazolone, tetrahydroisoquinolin-one, tetrahydrobenzodiazepine-one, hexahydrobenzazocin-one, and the like. However, it is sufficient that a cyclic amide is present in the structural formula, and the present invention is not limited thereto.

Some cyclic amides may be derived from a single ring or a condensed heterocyclic ring, and the condensed heterocyclic ring is preferably a condensed heterocyclic ring with a phenyl ring. In this case, the phenyl ring may be substituted by a lower alkyl group having 1 to 6 carbon atoms, preferably a methyl group, a lower alkoxy group having 1 to 6 carbon atoms, preferably a methoxy group or a halogen atom.
Preferred examples are as follows.

In the above formula, Y in the formulas (i) and (l) means a hydrogen atom or a lower alkyl group, V in the formula (k) means a hydrogen atom or a lower alkoxy group, and the formulas (m), ( W ¹ and W ² in n) are independently the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and W ³ represents a hydrogen atom or a lower alkyl group. U in Formula (j) means a hydrogen atom, a lower alkyl group, or a lower alkoxy group.
In the formulas (j) and (l), the right ring is a 7-membered ring, and in the formula (k), the right ring is an 8-membered ring.
In the definition of J, (d) the group “lower alkyl group” is as described above.
Among the above definitions of J, preferred are (a) a group included in the group, (b) a group included in the group, and (c) a group included in the group, and most preferable is the group (b). And a monovalent group derived from an indanone (indanonyl) optionally substituted on the phenyl ring, or a monovalent group derived from a cyclic amide compound of (c) group.

<About B>

When R ² is a hydrogen atom, it is represented by the formula — (CH ₂ ) _n —, and further means that one or more methyl groups may be bonded to any carbon atom of the alkylene chain. . In this case, n is preferably 1 to 3.
In B, “dialkylaminoalkylcarbonyl group” means, for example, N, N-dimethylaminoalkylcarbonyl group, N, N-diethylaminoalkylcarbonyl group, N, N-diisopropylaminoalkylcarbonyl group, N-methyl-N-ethyl Mention may be made of aminoalkylcarbonyl groups.
In addition, in the series of groups of B, a case where an amide group is included in the group is also one of preferable groups.
More preferable group is represented by the formula —CH═CH— (CH) _n R ² — (wherein n represents 0 or an integer of 1 to 10, and R ² represents a hydrogen atom or a methyl group). A group represented by the formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a formula = CH- (CH ₂ ) _c- (where c is A group represented by the formula = (CH-CH) _d = (wherein d represents an integer of 0 or 1 to 5), a formula -NH A group represented by-, a group represented by the formula -O-, or a group represented by the formula -S-.

<About T, Q, q>

<K, bond>
“Substituted or unsubstituted phenyl group”, “substituted or unsubstituted arylalkyl group (which may be substituted with a phenyl group)”, “cinnamyl group with which a phenyl group may be substituted”, “substituted” in the definition of K In the “cycloalkyl group which may be substituted”, the substituent is the same as defined in (1) to (7) of the group (a) in the above definition of J. Preferably, it may be unsubstituted or substituted with a nitro group, a lower alkyl group such as methyl, or a halogen such as fluorine.
An arylalkyl group means that the phenyl ring is substituted with the above substituents, or an unsubstituted benzyl group, phenethyl group, or the like.
Specific examples of the pyridylmethyl group include a 2-pyridylmethyl group, a 3-pyridylmethyl group, and a 4-pyridylmethyl group.

As for K, an arylalkyl group in which the phenyl group may be substituted, a substituted or unsubstituted phenyl group, a cinnamyl group in which the phenyl group may be substituted, and a cycloalkyl group in which the phenyl group may be substituted are most preferable.
Preferable arylalkyl groups specifically include, for example, a benzyl group, a phenethyl group, etc. In these, the phenyl group is substituted with a lower alkoxy group having 1 to 6 carbon atoms, a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group, or the like. It may be.

  As an example of the case of a double bond, the case of a divalent group derived from indanone in which the phenyl ring described above may be substituted, that is, the case of an indanolidenyl group can be mentioned.

  In the present invention, the above compound has an asymmetric carbon depending on the type of substituent, and optical isomers may exist, but it goes without saying that these belong to the scope of the present invention.

  To describe one specific example, when J has an indanone skeleton, it has an asymmetric carbon, so that geometric isomers, optical isomers, diastereomers, etc. may exist, all of which are included in the scope of the present invention. It is.

<Compound Group (A) If these definitions are combined to give a particularly preferred compound group, a compound group (A) represented by the following general formula can be exemplified.

Wherein J ¹ is a monovalent or divalent group derived from a group selected from the following group optionally substituted with a phenyl group;
(1) Indanyl,
(2) Indanonyl,
(3) indenyl,
(4) Indenonyl,
(5) indandionyl,
(6) tetralonyl,
(7) Benzsuberonil,
(8) Indanolyl,
(9)

Or a pharmacologically acceptable salt thereof, or a solvate thereof.

In the above definition of J ¹ , the most preferable group includes an indanonyl group, an indanidonyl group, and an indanolidenyl group, which may be substituted with a phenyl group. In this case, the phenyl group may not be substituted, may be substituted with the same or different hydroxyl group, halogen, or lower alkoxy group, or may be substituted with an alkylenedioxy group between adjacent carbons of the phenyl ring. Most preferred. The lower alkoxy group means, for example, a methoxy group, an ethoxy group, an isopropoxy group, an n-propoxy group, an n-butoxy group or the like having 1 to 6 carbon atoms. preferable. Most preferred is the case where the methoxy group is disubstituted.

<About Compound Group B>
Among the compounds included in the formula (A), a further preferable group of compounds includes compounds represented by the following general formula (B).

[Wherein J ¹ has the same meaning as described above.

A hydrogen atom or a methyl group is meant. ), A group represented by the formula —CH═CH— (CH) _n R ² — (wherein n represents 0 or an integer of 1 to 10, and R ² represents a hydrogen atom or a methyl group). A group represented by the formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a formula = CH- (CH ₂ ) _c- (where c is Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5). B ¹ is preferably a group represented by the formula — (CH) _n R ² — (wherein n represents 0 or an integer of 1 to 10. R ² represents a hydrogen atom or a methyl group). More preferably, n = 1, R ² is —CH ₂ — of a hydrogen atom, or n = 3, R ² is —CH ₂ —CH ₂ —CH ₂ — of a hydrogen atom. B ¹ is preferably a formula —CH═CH— (CH) _n R ² — (wherein n represents an integer of 0 or 1 to 10, and R ² represents a hydrogen atom or a methyl group). More preferably, n = 1 and R ² is a hydrogen atom —CH═CH—CH ₂ —.

<About Compound Group (C)>
Among the compounds included in the formula (B), a more preferred compound group includes compounds represented by the following general formula (C).

<About Compound Group (D)>
Among the compounds included in the formula (C), a further preferable group of compounds includes compounds represented by the following general formula (D).

(Wherein J ² represents a monovalent or divalent group derived from indanonyl which may be substituted with a phenyl group (for example, indanonyl, indanolidenyl group), a group selected from indenyl and indandionyl, more preferably. is, J ² means a good indanonyl group which may have a lower alkyl group or a lower alkoxy group having 1 to 6 carbon atoms having 1 to 6 carbon atoms as a substituent.
K ¹ represents a substituted or unsubstituted phenyl group, an optionally substituted arylalkyl group, an optionally substituted cinnamyl group, or an optionally substituted cycloalkyl group.

Furthermore, particularly preferred compound groups (compound groups having ChE inhibitory activity) of the cyclic amine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof are as follows.
1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-ylidenyl) methylpiperidine,
1-benzyl-4-((5-methoxy-1-indanone) -2-yl) methylpiperidine,
1-benzyl-4-((5,6-methylenedioxy-1-indanone) -2-yl) methylpiperidine,
1- (m-nitrobenzyl) -4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine,
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine,
1- (m-fluorobenzyl) -4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine,
1-benzyl-4- (3-((5,6-dimethoxy-1-indanone) -2-yl) propyl) piperidine,
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone) -2-yl) methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-ylidenyl) propenylpiperidine, and 1-benzyl-4-((5,6-dimethoxy-1,3-indandione) -2 -Yl) propenylpiperidine, more preferably 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine.
<Manufacturing method>
The compound having ChE inhibitory activity, pharmacologically acceptable salt thereof, or solvate thereof used in the present invention can be produced by a known method, and is a cyclic amine represented by the general formula (I) As typical examples of the derivatives (for example, donepezil hydrochloride), JP-A-1-79151, Japanese Patent 2578475, Japanese Patent 2733203, Japanese Patent 3078244, or US Pat. No. 4,895,841. It can be easily manufactured by a method disclosed in a publication. Donepezil hydrochloride is also available as a preparation such as a fine granule.
Galantamine and its derivatives are disclosed in U.S. Pat. No. 4,663,318, WO 88/08708, WO 97/03987, U.S. Pat. No. 6,316,439, U.S. Pat. No. 6,323,195, U.S. Pat. It can be easily produced by the method disclosed in Japanese Patent No. 6323196.
Tacrine and its derivatives are disclosed in U.S. Pat. No. 4,631,286, U.S. Pat. No. 4,695,573, U.S. Pat. No. 4,754,050, WO 88/02256, U.S. Pat. No. 4,835,275, U.S. Pat. 4839364, US Pat. No. 4,999,430, International Publication No. WO97 / 21681, and the like.
Physostigmine and its derivatives are disclosed in US Pat. No. 5,077,289, US Pat. No. 5,177,101, US Pat. No. 5,302,721, JP-A-5-306286, US Pat. No. 7,166,824, and European Patent No. 298202. It can be easily produced by the method disclosed in the specification, WO 98/27096 pamphlet, J. Pharm. Exp. Therap., 249 (1), 194-202, 1989, and the like.
Rivastigmine and its derivatives can be easily produced by methods disclosed in European Patent No. 193926, International Publication No. 98/26775, International Publication No. 98/27055, and the like.
Commercially available compounds among these compounds can be easily obtained from chemical manufacturers.
In the present invention, pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, phosphate, formate, acetate, trifluoroacetate, maleate, Mention may be made of organic acid salts such as tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate.
Depending on the choice of the substituent, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt , N, N′−
Error 1: Replaced with ■ because there was a character outside the JPO regulations.
In some cases, organic amine salts such as dibenzylethylenediamine salts, ammonium salts, and the like are formed.
In the present invention, the compound having a ChE inhibitory action, or an pharmacologically acceptable salt thereof (for example, donepezil hydrochloride), which is an active ingredient for an ameliorating agent or therapeutic agent, may be an anhydride and hydrated. A solvate such as a product may be formed. In the present invention, the solvate is preferably a pharmacologically acceptable solvate. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferable. As the non-hydrate, alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide, dimethyl sulfoxide (DMSO) and the like can be used. For example, the donepezil may have a crystal polymorphism, but the present invention is not limited to this. Any crystal form may be a single crystal form or a crystal form mixture.
In the present invention, the above compound has an asymmetric carbon depending on the type of substituent, and optical isomers may exist, but it goes without saying that these belong to the scope of the present invention.
To describe one specific example, when J has an indanone skeleton, it has an asymmetric carbon, so that geometric isomers, optical isomers, diastereomers, etc. may exist, all of which are included in the scope of the present invention. It is.

2. Kami-Ongo-boiled water Kami-on-boiled water used in the present invention is a Chinese medicine having an activity-increasing action of choline acetyltransferase (ChAT). It contains 13 herbal medicines, licorice, Daegu, Ji-Huang, and Ginseng. Furthermore, in addition to the above-mentioned 13 constituent herbal medicines, Kamito Bokuto may contain one or more herbal medicines selected from the group consisting of Koren, Mumon Fuyu, Toki, and Azusa.

  In the present invention, Toshi, which is one of the constituent herbal medicines of Kami Onsen, has a remarkable ChAT activity increasing action and NGF inducing action with a single extract (Yamada Yojo, Yabe Takeshi, “Dementia and Kami Warm "Gyoto", Kampo and the latest treatment, Seiko Jihosha, Inc., August 15, 2001, Vol. 10, No. 3, P229-234). In other words, it is thought that Toshi is a crude drug with a central role in the central action of Kami Ongokuto.

  Accordingly, preferred Kampo for use in combination with or blended with a ChE inhibitor as a therapeutic agent for Alzheimer's disease in the present invention includes Kamibokuto or one of its constituent crude drugs. It is also possible to use other Chinese medicines, for example, Kami Ongokuto, at least one of herbal medicines in combination with a ChE inhibitor in addition to distant.

3. TECHNICAL FIELD The present invention relates to a therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder.

  The present invention is based on the knowledge that when a combination or combination of a ChE inhibitor and at least one of Kamiyokubokuto or its constituent crude drugs activates cholinergic nerves, it improves cognitive function and cerebral blood flow. is there. Therefore, a combination or combination of a ChE inhibitor and Kamibokuto is an active ingredient of a cerebral blood flow improving agent, a cognitive dysfunction improving agent with cerebrovascular disorder, or a therapeutic agent for Alzheimer's disease with cerebrovascular disorder. Useful. Since the above cerebral blood flow improvement effect is mainly observed in the frontal lobe, the therapeutic agent of the present invention is effective as an active ingredient of the frontal blood flow improvement agent.

In the present invention, “cerebral vascular disorder” means asymptomatic cerebral infarction in the basal ganglia and magnetic cerebral white matter lesion on MRI in Magnetic Resonance Imaging (MRI).
In the present invention, Alzheimer's disease is sometimes referred to as Alzheimer's disease, Alzheimer's dementia, Alzheimer's syndrome, and the like. The criteria for determining whether or not you have Alzheimer's disease are the “Diagnostic Standards for Alzheimer-type Dementia” in the “Guide for Diagnosis and Statistics of Mental Disorders” (DSM-IV) established in 1994 by the American Psychiatric Association, or NINCDS-ADRA standards are used internationally. The therapeutic agent of the present invention is effective for Alzheimer's disease patients with cerebrovascular disorders, but is preferably used for mild to moderate patients in the above criteria.

The present invention relates to a method for improving cognitive function associated with cerebrovascular disorder, and an effect of improving cerebral blood flow, characterized by administering an effective amount of a combined or combined agent of the ChE inhibitor of the present invention and Kamibokujito. Or a method of treating Alzheimer's disease.
“Treatment” generally means obtaining a desired pharmacological and / or physiological effect. The effect is prophylactic in terms of completely or partially preventing the disease and / or symptoms and therapeutic in terms of partial or complete cure of the adverse effects caused by the disease and / or disease. As used herein, “treatment” means any treatment of a disease in a patient mammal, particularly a human, and includes the meanings of the above general treatments. “Treatment” includes, for example, the following items (a) to (c):
(A) prevent a disease or symptom from occurring in a patient who may have a predisposition to the disease or symptom but has not yet been diagnosed;
(B) inhibit disease symptoms, ie prevent or delay its progression;
(C) Alleviating disease symptoms, ie, causing the disease or symptoms to reverse, disappear, or reverse the progression of symptoms.

A compound having a ChE inhibitory action or a salt thereof, or a solvate thereof, or a prodrug or a salt thereof, or a solvate thereof is administered to humans or non-human mammals in various forms, orally or parenterally (for example, intravenous injection). , Intramuscular injection, subcutaneous administration, rectal administration, and transdermal administration). The compound having a ChE inhibitory action or a salt thereof, or a solvate thereof, or a prodrug or a salt thereof, or a solvate thereof can be used alone, but can be used according to a method commonly used depending on the administration route. It can be formulated into an appropriate dosage form using a pharmaceutical carrier.
Preferred dosage forms include, for example, tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, etc. oral preparations, inhalants, suppositories, injections (including drops), ointments And parenteral preparations such as eye drops, eye drops, eye ointments, nasal drops, ear drops, patches, poultices, lotions, liposomes and the like.
Carriers used for formulating these preparations include, for example, commonly used solvents, excipients, coating agents, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, and stabilizers and emulsifiers as necessary. Absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, extenders, wetting agents, surface activators, dispersants, buffers, preservatives, solubilizers, suspending agents, A thickening agent, a soothing agent, an isotonic agent and the like can be used, and it is possible to formulate by a conventional method by blending components generally used as raw materials for pharmaceutical preparations. Non-toxic components that can be used include, for example, animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; esters such as octyldodecyl myristate and isopropyl myristate Oils; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; eg polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene -Surfactants such as polyoxypropylene block copolymers; eg hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, Water-soluble polymers such as livinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols (polyols) such as glycerin, propylene glycol, dipropylene glycol, sorbitol, and polyethylene glycol; such as glucose and sucrose For example, inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; inorganic salts such as sodium chloride and sodium phosphate; and purified water.
Examples of excipients include lactose, fructose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, Gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block copolymer, meglumine, etc., disintegrating agents such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, hydrogen carbonate Sodium, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc. Nesium, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, mint brain, aroma powder, mint oil, dragon brain , Cinnamon powder, etc. are used respectively. The component may be a salt thereof or a solvate thereof.
For example, an oral preparation is a compound having a ChE inhibitory action or a salt thereof or a solvate thereof, a prodrug or a salt thereof or a solvate thereof, an excipient, and if necessary, for example, a binder, a disintegrant, After adding a lubricant, a colorant, a flavoring agent, etc., a powder, a fine granule, a granule, a tablet, a coated tablet, a capsule or the like is prepared by a conventional method.
In the case of tablets and granules, coating is carried out in a well-known manner using coating agents such as carnauba wax, hydroxypropylmethylcellulose, macrogol, hydroxypropylmethylphthalate, cellulose acetate phthalate, sucrose, titanium oxide, sorbitan fatty acid ester, and calcium phosphate. May be.
Specific examples of carriers used for syrup preparation include sweeteners such as sucrose, glucose and fructose, arabic gum, tragacanth, carmellose sodium, methylcellulose, sodium alginate, crystalline cellulose, suspending agents such as beef gum, Dispersing agents such as sorbitan fatty acid ester, sodium lauryl sulfate, polysorbate 80 are listed. In producing the syrup, a flavoring agent, a fragrance, a preservative, a solubilizing agent, a stabilizer and the like can be added as necessary. Further, it may be in the form of a dry syrup that dissolves or suspends during use.
Injectable preparations are usually prepared by, for example, dissolving a salt of a compound having a ChE inhibitory action in distilled water for injection, but if necessary, a solubilizer, buffer, pH adjuster, isotonic agent, painless Additives, preservatives, stabilizers and the like can be formulated by conventional methods.
Sterilization of the injection may be performed by filtration sterilization using a filter, blending of a bactericide, and the like. Moreover, an injection can be manufactured as a form of preparation at the time of use. That is, it can be used as a sterile solid composition by lyophilization, etc., and dissolved in sterile water for injection or other solvent before use.
In the case of an external preparation, the production method is not particularly limited, and it can be produced by a conventional method. As the base material to be used, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used. For example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids , Silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water, etc. Agents, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances and the like can be added. An inhalant is a compound having a ChE inhibitory action or a salt thereof, or a solvate thereof, a prodrug or a salt thereof, or a solvate thereof, for administration by inhalation. It can be delivered from other convenient modes of delivering aerosol sprays. The pressure pack can contain a suitable propellant. In addition, for administration by inhalation, a compound having a ChE inhibitory action or a salt thereof or a solvate thereof, a prodrug or a salt thereof or a solvate thereof is in the form of a dry powder composition or in the form of a liquid spray. Can also be administered. When administering by transdermal absorption as a patch, it is preferable to select a so-called free body that does not form a salt. For topical administration to the epidermis, compounds with ChE inhibitory action can be formulated as ointments, creams or lotions, or as active ingredients for transdermal patches. Ointments and creams can be formulated, for example, by adding a suitable thickening and / or gelling agent to an aqueous or oily base. Lotions can be formulated with an aqueous or oily base and will in general contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, and / or coloring agents. You can also. A compound having ChE inhibitory activity can also be administered by iontophoresis.
Furthermore, components such as blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, moisturizers, and keratolytic agents can be blended as necessary. The ratio of the active ingredient to the carrier at this time can vary between 1 and 90% by weight.
The improving agent or therapeutic agent used in the present invention is usually 0.5% of a compound having a ChE inhibitory action or a salt thereof or a solvate thereof, a prodrug or a salt thereof or a solvate thereof as an active ingredient. It can be contained in a proportion of not less than wt%, preferably 10 to 70 wt%.
When a compound having a ChE inhibitory action or a salt thereof or a solvate thereof or a prodrug or a salt thereof or a solvate thereof is used for the treatment, it is at least 90% or more, preferably 95% or more, more preferably Is preferably 98% or more, more preferably 99% or more.
The dose of a compound having a ChE inhibitory action or its salt or a solvate thereof or a prodrug or a salt thereof or a solvate thereof after oral administration is determined by, for example, the administration route, the type of disease, the degree of symptom, As part of age, gender, body weight, salt type, specific type of disease, pharmacological findings such as pharmacokinetics and toxicological characteristics, whether drug delivery systems are used, and other drug combinations Although it varies depending on various factors including whether or not to be administered, it can be appropriately set by those skilled in the art. For example, per adult (60 kg), about 0.001-1000 mg / day, preferably about 0.01-500 mg / day, more preferably about 0.1-300 mg / day, once or several times Can be administered separately. When administered to children, the dose may be less than that administered to adults. The actual administration method used may vary widely and may deviate from the preferred administration methods described herein. For example, in the case of donepezil hydrochloride, it is preferably about 0.1 to 300 mg / day, more preferably about 0.1 to 100 mg / day, and further preferably about 1.0 to about 100 mg / day per adult (body weight 60 kg). 50 mg / day. In a preferred embodiment of donepezil hydrochloride, 5 mg tablet or 10 mg tablet donepezil hydrochloride commercially available as trade name Aricept Tablets (Eisai Co., Ltd.) and donepezil hydrochloride of trade name Aricept Fine Granules (Eisai Co., Ltd.) can be administered. For example, a tablet can be administered from 1 to about 4 times a day. In a preferred embodiment, one 5 mg tablet or 10 mg tablet of the trade name Aricept Tablet (Eisai Co., Ltd.) is administered once a day. Those skilled in the art will appreciate that when donepezil hydrochloride is administered to children, the dosage may be less than that administered to adults, and in preferred embodiments, children receive about 0.5-10 mg / day of donepezil hydrochloride. It can be administered on a daily basis, preferably about 1.0-3 mg / day. In the case of tacrine, it is about 0.1 to 300 mg / day, preferably about 40 to 120 mg / day per adult (body weight 60 kg), and in the case of rivastigmine, about 0.1 per adult (body weight 60 kg). 1 to 300 mg / day, preferably about 3 to 12 mg / day, in the case of galantamine, about 0.1 to 300 mg / day, preferably about 16 to 32 mg / day, per adult (body weight 60 kg) In the case of physostigmine, it is about 0.1 to 300 mg / day, preferably about 0.6 to 24 mg / day, per adult (body weight 60 kg). In each case, when administered to children, the dose may be less than the amount administered to an adult.
In the case of parenteral administration, in the case of a patch, a preferable dose is about 5 to 50 mg / day, more preferably about 10 to 20 mg / day, per adult (60 kg). In the case of an injection, it is dissolved or suspended in a pharmacologically acceptable carrier such as physiological saline or commercially available distilled water for injection so as to have a concentration of 0.1 μg / ml carrier to 10 mg / ml carrier. It can be produced by becoming cloudy. The dosage of the injection thus prepared is about 0.01 to 50 mg / day, preferably about 0.01 to 50 mg / day for an adult (60 kg) per patient requiring treatment. The dose is 5.0 mg / day, more preferably about 0.1 to 1.0 mg / day, and can be administered in 1 to 3 divided doses per day. When administered to children, the dose may be less than that administered to adults.

  The prescription for Kamibokuto, which is the active ingredient of the therapeutic agent of the present invention, is described in the classics of Kampo prescriptions such as Tenrikata Norin, Sengokukata, Rejuvenated Manju, etc. Is generally as follows. However, the prescription of the kamisen hot boiled water of the present invention is not limited to this.

  Half-summer 3.5-6, Chen 0-5, ginger 0.5-3, bamboo basket 2-5, coconut 1-5, Zhi 0-2, acid jinjin 0-5, cocoon 3-6, carrot 0 3, licorice 1-2, Daegu 0-2, ground yellow 0-2, ginseng 0-2, yellow ream 0-2, Mumon winter 0-3, return 0-2, cinnabar 0-1.

  The present invention also provides the above 2. As mentioned above, in addition to the above-mentioned Kamisenbokuto as a preferred Kampo to be used in combination with or blended with a ChE inhibitor, it may include a long-distance that is a constituent herbal medicine of Kamiunto, or a Kampo that contains aspiration it can.

  As a therapeutic agent of the present invention, a ChE inhibitor that is used in combination with Kami Ongokuto or Distant, or is compounded with Kami Ongokuto or Distant is a compound having a ChE inhibitory action or a pharmacologically acceptable salt ( For example, donepezil hydrochloride) can be used as it is, or it can be formulated by blending a known pharmaceutically acceptable carrier.

  In addition, as the therapeutic agent of the present invention, Kami Ongokuto or Toshi used in combination with ChE inhibitor or blended with ChE inhibitor is used in the above-described combination of Kami Ongyoto or Toshi, Kami Ongyoto or Toshi It is also possible to use a medicine or a traditional Chinese medicine containing a long-distance as it is, or a combination with a known pharmaceutically acceptable carrier or the like. Kami Ongokuto and other nicks or extract preparations containing Enshi (e.g. Kaki Kisui, Ninjin Yoei) include Enshi.

  Examples of the Kashiwa Gyoto or Distant extract include various water-based solvent extracts of Kamiyu Gyoto or Enshi, and it is preferable to use a water extract. As a specific example of preparation of an extract of Kamibokubyoto or Toshi, there is a method of extracting Kamiyutobyoto or Zushi with the above composition with 10 to 20 times the amount of hot water and filtering the obtained extract. Can be mentioned. This extract can be dried as needed and used as a dry powder.

  For example, according to the description of the classic “Shokan Noriori”, add about 600 ml of water to a 31.5 g pack of 13 kinds of herbs, decoct to about half amount (300 ml), remove the decoction, The liquid can be taken 1 to 3 times a day. In addition, a Kampo extract preparation can be used in consideration of ease of taking and convenience of carrying.

Specific examples of the dry preparation are as follows.
Semi-summer, Chen skin, bamboo shoots, coconuts, potatoes 5g each, Enshi, acid soy sauce, carrots, licorice, daikon, ground yellow, ginseng 2g each, ginger 0.5g (Kamito hot boiled water: 31.5g) After adding 600 ml of distilled water to the mixed herbal medicine and decocting to half volume, the resulting extract is filtered and freeze-dried to obtain 8.08 g of dry extract.

  It is preferable that the therapeutic agent of the present invention is used in combination with a ChE inhibitor and Kamibokuto. A ChE inhibitor and distant can also be used in combination. Furthermore, a ChE inhibitor and Kamibokuto or a distant medicinal extract component can be used in combination. In combination, the effective amount may be taken as it is or as a formulation at the same time. In addition, when using a long-distance together, other herbal medicines, for example, one or more herbal medicines other than the long-distance composing Kami Ongokuto can be added, but in the following description, the type of use for the long-distance is described. To do.

  In addition, the therapeutic agent of the present invention can also be used as a compounding agent in which Kamibokuto is blended with a ChE inhibitor. Other examples of combinations of such combinations include Choshi inhibitor for Choshi, ChE inhibitor Kamiyokubyoto or Kishiyokubyoto extract, Kishiyokubyoto for ChE inhibitor, and Chase for ChE. The combination which mix | blends a ChE inhibitor with the inhibitory agent or a medicinal extract component of a seasoning hot boiled water or distant is mentioned. The compounding may be performed after preparing each of the basic drug and the drug to be blended after preparing to some extent, and may be formulated by combining pharmaceutically acceptable carriers in some cases. A combination of acceptable carriers and the like may be formulated. A person skilled in the art can formulate a compounding agent based on a known technique.

  Moreover, the dosage form of the therapeutic agent for Alzheimer's disease of the present invention is not particularly limited, and can be administered orally or parenterally. At the time of combined use or combination, the dosage form and dose of the ChE inhibitor and Kamisengoto or distant may be different.

  For example, as an oral administration form of ChE inhibitor, Donepezil hydrochloride fine granules can be obtained as trade name Aricept fine granules (Eisai Co., Ltd.), and tablets can be obtained as trade name Aricept tablets (Eisai Co., Ltd.). As an oral dosage form of Kamibokubyoto or Distant, decoction can be mentioned. Alternatively, the form of parenteral administration of the therapeutic agent for Alzheimer's disease of the present invention includes percutaneous absorption, intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, intraperitoneal injection, etc., preferably intravenous injection. It is. Moreover, the injection for the Alzheimer's disease therapeutic agent of the present invention is a non-aqueous diluent (eg, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol), suspensions or emulsions. It can be prepared as Sterilization of the injection may be performed by filtration sterilization using a filter, blending of a bactericide, and the like. Moreover, an injection can be manufactured as a form of preparation at the time of use. In other words, ChE inhibitor or Kamibokubyoto or distant extract (or extract) is made into a sterile solid composition by lyophilization, etc., and dissolved in sterile water for injection or other solvents before use. Can be used. When administered by transdermal absorption as a patch, it is preferable to select a so-called free body that does not form a salt as the cholinesterase inhibitor.

The dose of the above-mentioned Kamibokuto in oral administration is 0.1 to 300 g / day, preferably 1 to 300 g / day, more preferably 10 to 50 g / day. The dose of distant as a constituent crude drug is 0.01 to 20 g / day, preferably 0.1 to 20 g / day, more preferably 1 to 5 g / day.
Moreover, in the case of an injection, Kamibokubisoto is added to a concentration of 0.1 μg / ml carrier to 10 mg / ml carrier in a pharmaceutically acceptable carrier such as physiological saline or commercially available distilled water for injection. Alternatively, it can be produced by dissolving or suspending a distant dry powder or the like. The dose of the souped soy sauce or distant injection prepared in this way is 0.1-100 mg / day, more preferably 0.1-10 mg / day, for patients who require treatment. It can be divided into 1 to 3 times per day.
The dose at the time of the combined use or combination drug can be appropriately selected from the above doses.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited by a present Example.

  50 patients with mild-moderate AD who have not been treated according to the NINCDS-ADRDA criteria, 20 patients with Donepezil-treated group, KUT-treated group Eleven persons and 19 persons in combination with donepezil hydrochloride and Kamibokujito (Donepezil plus KUT (combined) treated group) were entered in this example. Table 1 shows the characteristics before administration (baseline) for the patients entered in this example.

  In Table 1, “No. of patients enrolled” is the number of patients entered in this example, “No. of patients studied” is the number of patients examined, and “gender (M / F)” is gender (male / female). ), "Age" is age, "MMSE" is Mini-Mental State Examination, "ADAS-cog." Is Alzheimer's Disease Assessment Scale (Alzheimer's Disease Assessment Scale Cognitive Function Test), "CSF-tau" Is a cerebrospinal fluid tau protein, "Silent brain infarction" is asymptomatic cerebral infarction, "Deep white matter lesion" is a deep white matter lesion, and "Peri-ventricular white matter lesion" is a pericerebral white matter lesion. Here, ADAS-cog. Is used as an international standard to see changes in cognition. The three items “Silent brain infarction”, “Deep white matter lesion” and “Peri-ventricular white matter lesion” are MRI findings indicating vascular disorder.

  As shown in Table 1, at baseline, there was no significant difference in age, gender, and ADAS-cog. In the combination group, 21.1% of patients have Silent brain infarction. For deep white matter lesions and peri-ventricular white matter lesions, larger numbers indicate stronger ischemic lesions. Deep white matter lesions are most noticeable in the combination group.

Next, the following groups were administered to AD patients having the characteristics shown in Table 1.
In the donepezil-treated group, donepezil hydrochloride 3 mg / day was administered in advance for 2 weeks, and after confirming that no side effects were observed, the dose was increased to 5 mg / day. The KUT-treated group is a 31.5g pack of 13 kinds of herbs added to 600ml of water, boiled to 300ml and decocted, 2 minutes a day, according to the description of Tensho Nozomi. It was clothes.
In the combination group, the same doses as those administered to the above-described donepezil hydrochloride alone group and the Kamitsutobisoto alone group were taken in the same amount. After 12 weeks from the start of administration in each of the above groups, evaluation was performed by DAS-cog. And quantitative SPECT imaging and compared with the baseline value.

The results are shown in Table 2.

  In Table 2, “*” indicates that the value of “Follow-up” is significantly different from “Baseline” (p <0.05), and “†” is significantly different from the values of other treatment groups. (P <0.05). medial frontal is the medial frontal lobe, lateral frontal is the lateral frontal lobe, medial temporal is the medial temporal lobe, superior parietal is the upper parietal lobe, and medial occipital is the local occipital lobe. “Lt.” Indicates left and “rt.” Indicates right.

  As shown in Table 2, ADAS-cog. Showed no significant improvement by administration in the single administration group. On the other hand, in the combination administration group, p <0.0001 (paired t-test test) and significant improvement in cognitive function were recognized by administration (Table 2).

Next, 111 MBq of ¹²³ I-IMP (N-isopropyl- ¹²³ Ip-iodoamphetamine) was administered using a 3-detector gamma camera, and the ARG method (Inoue K, et al., Ann Nucl Med. 16 (5 ): 311-316, 2002.) The cerebral blood flow count value was corrected and SPECT quantitative images were prepared. Data analysis was statistical test using ROI method and SPM99 soft-wear.

  The results are shown in FIG. A and B in FIG. 1 show that no increase in cerebral blood flow is observed before and after administration in the KUT-treated group and the donepezil hydrochloride alone group. C, D, and E in FIG. 1 indicate the increased site of cerebral blood flow in the frontal lobe in yellow in the Kamibokubyoto-Donepezil hydrochloride combined group (Donepezil plus KUT (compined) treated group). BA is an abbreviation for Broadman area and indicates each part of the brain, and the Z value indicates a significant difference test value. F, G, and H on the left side of FIG. 1 are views of an increase in cerebral blood flow in the combination administration group from various angles (F is lateral, G is forward, and H is horizontal). In F, G, and H, the point where the solid line intersects is the origin, the left and right sides of the brain are the x axis (the right hemisphere is +), the front and rear of the brain are the y axis (the frontal is +), and the upper and lower sides of the brain are the z axis ( Each position of the brain was expressed in coordinates with the top of the head as +). The position of the wedge shown in red in F, G, and H corresponds to the position where the solid lines intersect in C of FIG. Similarly, the wedge shown in green corresponds to D in FIG. 1, and the wedge shown in orange corresponds to the intersection in E of FIG.

  There was no significant difference in cerebral blood flow counts between the three groups at baseline. Next, a significant difference test was performed before and after administration. Regions where cerebral blood flow was significantly improved were colored white to yellow in C to E in FIG. 1 and black to gray in F to H. In the single administration group, no significant improvement region was observed, but in the combination group, a wide and significant cerebral blood flow improvement region was observed in the frontal lobe, mainly in the prefrontal cortex (p <0.05, corrected test) (Fig. 1). The position where the cerebral blood flow increased by administration was indicated by a wedge. The red wedge has coordinates (x, y, z) = (-16,34,36), BA 8,32, Z = 5.52, and the green wedge has coordinates (x, y, z) = (8,50 24), BA 9,10, Z = 5.58, the orange wedge had coordinates (x, y, z) = (− 36,32,2), BA 45,47, Z = 5.54.

  When there is a vascular disorder, it is the frontal lobe where blood flow is most affected by the effect. Therefore, it is considered that the present invention showing a significant blood flow improvement effect in the frontal lobe by the combined use of donepezil hydrochloride and Kamikanto is important. In addition, there were no cases where the combination therapy showed enhanced side effects specific to donepezil.

  From the above results, it was considered that the combination therapy of donepezil hydrochloride and Kamitsu-gokuto may be a treatment for Alzheimer's disease showing a synergistic effect of improving brain function.

It is the figure which showed the SPECT quantitative photography elephant and its result in the Kamiyu-gokutou single group, the donepezil hydrochloride single group, and a combined use group.

Claims (19)

  A cerebral blood flow improving agent comprising a compound having a cholinesterase inhibitory action, a pharmacologically acceptable salt thereof, or a solvate thereof, and at least one of Kamibokuto or its constituent crude drugs.   The remedy according to claim 1, wherein the brain is the frontal lobe.   A drug for improving cognitive dysfunction associated with cerebrovascular disorder, comprising a compound having a cholinesterase inhibitory action, a pharmacologically acceptable salt thereof, or a solvate thereof, and at least one of Kamiyutobyoto or its constituent crude drugs.   A therapeutic agent for Alzheimer's disease associated with cerebrovascular disorder, comprising a compound having a cholinesterase inhibitory action, a pharmacologically acceptable salt thereof, or a solvate thereof, and at least one of Kamisento or its constituent crude drugs. The improving agent or therapeutic agent according to any one of claims 1 to 4, wherein the compound having a cholinesterase inhibitory action is a cyclic amine derivative represented by the following general formula.
[Wherein, J represents (a) a substituted or unsubstituted group; (1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexyl group, (6) quinoxalyl group or (7) furyl group,
(B) a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group; (1) indanyl, (2) indanonyl, (3) indenyl, (4) Indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, formula (9)
(C) a monovalent group derived from a cyclic amide compound,
(D) Lower alkyl group, or (e) Formula R ¹ —CH═CH— (wherein R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group)
Means a group represented by
(Wherein R ³ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group),
A hydrogen atom or a methyl group is meant. }, A group represented by formula = (CH—CH═CH) _b — (wherein b represents an integer of 1 to 3), formula = CH— (CH ₂ ) _c — (where c is 0) Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5),
Or a group represented by the formula -NH-, a group represented by the formula -O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.
T means a nitrogen atom or a carbon atom.
K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group.
q means an integer of 1 to 3.
  J consists of substituted or unsubstituted (1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexyl group, (6) quinoxalyl group and (7) furyl group The remedy or therapeutic agent according to claim 5, which is one group selected from the group.   The improving agent or therapeutic agent according to claim 5, wherein J is a monovalent group derived from a cyclic amide compound. The improving agent or therapeutic agent according to any one of claims 1 to 4, wherein the compound having a cholinesterase inhibitory action is a cyclic amine derivative represented by the following general formula.
[Where,
J ¹ is a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group; (1) indanyl, (2) indanonyl, (3) indenyl, (4) Indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, formula (9)
(Wherein R ³ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group),
A hydrogen atom or a methyl group is meant. }, A group represented by formula = (CH—CH═CH) _b — (wherein b represents an integer of 1 to 3), formula = CH— (CH ₂ ) _c — (where c is 0) Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5),
Or a group represented by the formula -NH-, a group represented by the formula -O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.
T means a nitrogen atom or a carbon atom.
K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group.
q means an integer of 1 to 3.
B is the formula
A hydrogen atom or a methyl group is meant. A group represented by the formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a formula = CH- (CH ₂ ) _c- (wherein C represents an integer of 0 or 1 to 9) or a group represented by the formula = (CH-CH) _d = (wherein d represents an integer of 0 or 1 to 5). The therapeutic agent according to claim 8. The improving agent or therapeutic agent according to any one of claims 1 to 4, wherein the compound having a cholinesterase inhibitory action is a cyclic amine derivative represented by the following general formula.
[Where,
J ¹ is a monovalent or divalent group derived from a group selected from the following group optionally substituted by a phenyl group; (1) indanyl, (2) indanonyl, (3) indenyl, (4) Indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, formula (9)
A hydrogen atom or a methyl group is meant. A group represented by the formula: —CH═CH— (CH) _n R ² — (wherein n represents 0 or an integer of 1 to 10, and R ² represents a hydrogen atom or a methyl group). A group represented by the formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a formula = CH- (CH ₂ ) _c- (where c is Or a group represented by the formula = (CH-CH) _d = (wherein d represents 0 or an integer of 1 to 5).
K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group in which the phenyl group may be substituted, a cinnamyl group in which the phenyl group may be substituted, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, an optionally substituted cycloalkyl group, a lower alkoxycarbonyl group or an acyl group. ]   The remedy or therapeutic agent according to claim 10, wherein K is a substituted or unsubstituted arylalkyl group or phenyl group. Monovalent radicals and divalent group J ¹ is derived from indanonyl, which is one of the group selected from the group consisting of indenyl and indandionyl, improvement or therapeutic agents according to claim 10 or 11, wherein. J ¹ is a lower alkyl group or a lower alkoxy group which may indanonyl group have 1 to 6 carbon atoms having 1 to 6 carbon atoms as a substituent, claim 10 or 11 improving agent or therapeutic agent according.   The cyclic amine derivative is 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanone)- 2-Iridenyl) methylpiperidine, 1-benzyl-4-((5-methoxy-1-indanone) -2-yl) methylpiperidine, 1-benzyl-4-((5,6-methylenedioxy-1-indanone) ) -2-yl) methylpiperidine, 1- (m-nitrobenzyl) -4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine, 1-cyclohexylmethyl-4-((5 , 6-Dimethoxy-1-indanone) -2-yl) methylpiperidine, 1- (m-fluorobenzyl) -4-((5,6-dimethoxy-1-indanone) -2-yl) Tilpiperidine, 1-benzyl-4- (3-((5,6-dimethoxy-1-indanone) -2-yl) propyl) piperidine, 1-benzyl-4-((5-isopropoxy-6-methoxy-) 1-indanone) -2-yl) methylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-ylidenyl) propenylpiperidine, and 1-benzyl-4-((5,6 The improvement or therapeutic agent according to claim 5, which is at least one selected from the group consisting of -dimethoxy-1,3-indandione) -2-yl) propenylpiperidine.   The improving agent or therapeutic agent according to claim 5, wherein the cyclic amine derivative is 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine.   The compound having a cholinesterase inhibitory action is 1-benzyl-4-((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine hydrochloride, according to any one of claims 1 to 4. The improving agent or therapeutic agent described.   The remedy or therapeutic agent according to any one of claims 1 to 4, wherein the compound having a cholinesterase inhibitory action is galantamine, tacrine, physostigmine or rivastigmine.   The remedy or therapeutic agent according to any one of claims 1 to 17, wherein the constituent herbal medicine of Kami Ongokuto contains at least distant.   A compound having a cholinesterase inhibitory action according to any one of claims 1 to 17, a pharmacologically acceptable salt thereof, or a solvate thereof, and at least one of Kamiyokuto or its constituent crude drugs to a patient. A method for treating Alzheimer's disease associated with cerebrovascular disorder, which comprises administration.